digoxin and Colorectal-Neoplasms

Digoxin has been shown to affect a number of pathways that are of relevance to cancer, and its use has been associated with increased risks of breast and uterus cancer and, more recently, a 40% increase in colorectal cancer risk. These findings raise questions about the safety of digoxin use in colorectal cancer patients, and, therefore, we investigated whether digoxin use after colorectal cancer diagnosis increased the risk of colorectal cancer-specific mortality.. A cohort of 10,357 colorectal cancer patients newly diagnosed from 1998 to 2009 was identified from English cancer registries and linked to the UK Clinical Practice Research Datalink (to provide digoxin and other prescription records) and to the Office of National Statistics mortality data (to identify 2,724 colorectal cancer-specific deaths). Using time-dependent Cox regression models, unadjusted and adjusted HRs and 95% confidence intervals (CI) were calculated for the association between postdiagnostic exposure to digoxin and colorectal cancer-specific mortality.. Overall, 682 (6%) colorectal cancer patients used digoxin after diagnosis. Digoxin use was associated with a small increase in colorectal cancer-specific mortality before adjustment (HR, 1.25; 95% CI, 1.07-1.46), but after adjustment for confounders, the association was attenuated (adjusted HR, 1.10; 95% CI, 0.91-1.34) and there was no evidence of a dose response.. In this large population-based colorectal cancer cohort, there was little evidence of an increase in colorectal cancer-specific mortality with digoxin use after diagnosis.. These results provide some reassurance that digoxin use is safe in colorectal cancer patients.

Topics: Aged; Aged, 80 and over; Colorectal Neoplasms; Digoxin; Female; Humans; Male; Middle Aged; Survival Analysis

Cardiac glycosides affect several pathways central for tumor formation. We sought to evaluate the association between digoxin use and colorectal cancer (CRC) risk.. We conducted a nested case-control study using The Health Improvement Network (THIN), a medical record database representative of the broader UK population. Study cases were defined as those with a diagnostic code for CRC. Each case was matched to up to four eligible controls on age, sex, practice site, and duration of follow-up before index date using incidence density sampling. Exposure of interest was digoxin therapy before index date. The odds ratios (ORs) and 95% confidence intervals (CIs) for CRC associated with digoxin use were estimated using conditional logistic regression analysis, adjusted for BMI, alcoholism, smoking history, diabetes mellitus, heart disease, chronic NSAIDs use and previous screening colonoscopies.. The case-control analysis included 20 990 CRC patients and 82 054 controls whose mean follow-up time before index date was 6.5 years (SD 4.0). The adjusted OR for CRC among current digoxin users was increased compared with non-users with an adjusted ORs of 1.41 (95%CI 1.25-1.59, p < 0.0001), 1.45 (95%CI 1.22-1.72, p < 0.0001) and 1.41 (95%CI 1.00-1.99, p = 0.049) for first prescriptions 1-5 years, 5-10 years and more than 10 years before index date respectively. Similar results were observed when cumulative duration and number of digoxin prescriptions were analyzed. The risk was not elevated for past digoxin users.. Current digoxin use is associated with increased CRC risk.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Alcoholism; Anti-Inflammatory Agents, Non-Steroidal; Body Mass Index; Case-Control Studies; Colorectal Neoplasms; Comorbidity; Digoxin; Female; Humans; Incidence; Male; Middle Aged; Risk Factors; Sex Factors; Smoking

[3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-phenyl]-((S)-3-hydroxy-3-piperidin-2-yl-azetidin-1-yl)-methanone (GDC-0973) is a potent and highly selective inhibitor of mitogen-activated protein kinase(MAPK)/extracellular signal-regulated kinase (ERK) 1/2 (MEK1/2), a MAPK kinase that activates ERK1/2. The objectives of these studies were to characterize the disposition of GDC-0973 in preclinical species and to determine the relationship of GDC-0973 plasma concentrations to efficacy in Colo205 mouse xenograft models. The clearance (CL) of GDC-0973 was moderate in mouse (33.5 ml · min(-1) · kg(-1)), rat (37.9 ± 7.2 ml · min(-1) · kg(-1)), and monkey (29.6 ± 8.5 ml · min(-1) · kg(-1)). CL in dog was low (5.5 ± 0.3 ml · min(-1) · kg(-1)). The volume of distribution across species was large, 6-fold to 15-fold body water; half-lives ranged from 4 to 13 h. Protein binding in mouse, rat, dog, monkey, and human was high, with percentage unbound, 1 to 6%. GDC-0973-related radioactivity was rapidly and extensively distributed to tissues; however, low concentrations were observed in the brain. In rats and dogs, [(14)C]GDC-0973 was well absorbed (fraction absorbed, 70-80%). The majority of [(14)C]GDC-0973-related radioactivity was recovered in the bile of rat (74-81%) and dog (65%). The CL and volume of distribution of GDC-0973 in human, predicted by allometry, was 2.9 ml · min(-1) · kg(-1) and 9.9 l/kg, respectively. The predicted half-life was 39 h. To characterize the relationship between plasma concentration of GDC-0973 and tumor growth inhibition, pharmacokinetic-pharmacodynamic modeling was applied using an indirect response model. The KC(50) value for tumor growth inhibition in Colo205 xenografts was estimated to be 0.389 μM, and the predicted clinical efficacious dose was ∼10 mg. Taken together, these data are useful in assessing the disposition of GDC-0973, and where available, comparisons with human data were made.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Autoradiography; Azetidines; Bile; Brain; Cell Line, Tumor; Cell Membrane; Cell Membrane Permeability; Colorectal Neoplasms; Dogs; Dose-Response Relationship, Drug; Female; Humans; Injections, Intravenous; Macaca fascicularis; Male; Mice; Mice, Nude; Microsomes, Liver; Models, Biological; Piperidines; Predictive Value of Tests; Prospective Studies; Protein Kinase Inhibitors; Rats; Rats, Long-Evans; Rats, Sprague-Dawley; Retrospective Studies; Species Specificity; Tissue Distribution; Xenograft Model Antitumor Assays

5-Fluorouracil, a widely used drug in cancer treatment, is known to have cardiotoxic effects: chest pain with ECG changes, arrhythmias, arterial hypertension or hypotension, myocardial infarction, cardiogenic shock and sudden death have been described in the literature. Coronary artery vasospasm is the pathogenetic mechanism hypothesized in most cases, but mechanisms other than myocardial ischemia had been advocated in some patients. The approach to the patient with persistent chest pain, despite therapy and persistent ST-segment elevation mimicking an acute myocardial infarction, has not been well addressed, and the appropriate diagnostic and therapeutic pathways have not yet been defined. We present our experience regarding 2 patients treated with 5-fluorouracil and referred to our coronary care unit because of prolonged chest pain (in one case with clinical evidence of hemodynamic impairment) and persistent ST-segment elevation, in whom an acute myocardial infarction was suspected. One patient was treated with systemic fibrinolysis, and coronary angiography was performed 6 days later; the other was submitted to urgent coronary angiography shortly after admission. In both cases the ECG and echocardiographic abnormalities were transient and normalized within a few days, the serum markers of myocardial necrosis were persistently in the normal range and the coronary artery trees were normal. The diagnostic and therapeutic approach to patients with this unusual clinical presentation is also discussed.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Anti-Arrhythmia Agents; Antimetabolites, Antineoplastic; Atrial Fibrillation; Captopril; Chest Pain; Colorectal Neoplasms; Coronary Angiography; Digoxin; Disease Management; Echocardiography; Electrocardiography; Fluorouracil; Humans; Laryngeal Neoplasms; Middle Aged; Myocardial Infarction; Nitrates; Verapamil